Inflammatory diseases of the skin, such as psoriasis and atopic dermatitis, afflict greater than 5% of the population. Currently, the treatment of these disorders typically involves the use of topical steroids. However, these agents also have undesirable side effects such as skin atrophy which limit the duration of therapy. In addition, topical application of a drug is difficult for many patients where the affected area may be very large.
Phospholipase A2 (PLA2) is the common name for phosphatide 2-acylhydrolase which catalyzes the hydrolysis of the sn-2-acyl ester bond of phosphoglycerides and results in production of lysophospholipids and free fatty acids. When the fatty acid is arachidonic acid, further action by cyclooxygenase and 5-lipoxygenase enzymes results in eicosanoid production, which is implicated in inflammation, and leukotrienes which are linked to asthma. Lysophophospholipid metabolism results in production of platelet activating factor and both lysophospholipids and platelet activating factor also play a role in inflammation.
PLA2 enzymes existas secreted forms (MWxcx9c12,000-15,000) and cytosolic forms (MWxcx9c85,000). The cytosolic or cPLA2 enzymes appear to play a key role in the pathway leading to the formation of platelet activating factor and the eicosanoids.
Inappropriate activation of the cytosolic PLA2 enzymes, therefore, can result in a variety of chronic and acute conditions including asthma, cerebral ischemia (Clemens et al, Stroke 1996, 27, 527-535), Alzheimer""s Disease (Stephenson et al, Neurobiology of Stroke, 1996, 3, 51-63 and see also U.S. Pat. No. 5,478,857), rheumatoid arthritis, neutrophil and platelet activation (Huang et al, Mediators of Inflammation 1994, 3, 307-308), chronic skin inflammation and damage to the skin resulting from exposure to ultraviolet light (Gresham et al., American Journal of Physiology, 1996, 270; Cell Physiology 39:C1037-C1050) and macrophage activation (Balsinde et al, Journal of Biological Chemistry, 1996, 271, 6758-6765).
Selective inhibitors of the cPLA2 enzymes may, therefore, be of use in controlling a wide variety of inflammatory diseases. The literature describes a significant number of compounds said to be phospholipase A2 inhibitors, but few selective inhibitors for the cPLA2 enzymes are available. The present inventors had as their, goal the synthesis of novel compounds which would be selective and potent inhibitors of the cPLA2 enzymes. As used herein, the term xe2x80x9cselective inhibitors of the cPLA2 enzymesxe2x80x9d means that the inhibitors inhibit the cPLA2 enzymes with a potency 20-fold or greater than they inhibit the lower molecular weight synovial PLA2 enzymes.
Biochemistry 32: 5935-5940, 1993, discloses a trifluoromethyl ketone analog of arachidonic acid having the formula 
as a selective inhibitor of cPLA2.
Bioorganic Med. Chem. Lett. 5: 519-522, 1995, discloses selective cPLA2 inhibitors of the formula 
where R is either H or OH.
Japanese published patent application JP09268153A (Derwent No. 97-554679/51) discloses cPLA2 inhibitors of the formula RCOCF3 where RCO is an acyl residue of an n-3 series highly unsaturated fatty acid. The compounds are said to be useful as antiinflammatory or antiallergic drugs.
Published PCT Application WO 98/25893 discloses arylsulfonamide compounds of the general formula 
wherein
A represents a C4-C10 alkyl group, an aryl group, an arylalkyl group, radicals selected from the group consisting of xe2x80x94CHxe2x95x90CHxe2x80x94B,xe2x80x94Oxe2x80x94B,xe2x80x94Sxe2x80x94B, and xe2x80x94NHxe2x80x94B, or radicals of formula xe2x80x94CH2xe2x80x94X,
wherein
B represents a non-aromatic C3-C8 carbocycle, a C3-C8 alkyl group, a heterocycle or an arylalkyl group, each of which is optionally substituted with one or more members independently selected from the group consisting of a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, cyano, nitro, a heterocycle, an aryl group and an aryloxy group, and
X is a member selected from the group consisting of a halogen atom, xe2x80x94Sxe2x80x94aryl,xe2x80x94Sxe2x80x94heterocycle, and xe2x80x94PO3R2 wherein each R is independently selected from the group consisting of a hydrogen atom and C1-C3 alkyl;
R1 and R2 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula: xe2x80x94(CH2)qxe2x80x94Axe2x80x2 wherein q is an integer of 2 to 4, and Axe2x80x2 is a member selected from the group consisting of a hydroxyl group, a group represented by the formula: 
wherein R5 and R6 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula: 
wherein R7 represents a hydrogen atom, a lower alkyl group, or a group represented by the formula: 
wherein s is an integer of 2 to 5; or
R1 and R2 each independently represent an unsubstituted cycloalkyl group, or a cycloalkyl substituted with a lower alkyl or halogen or condensed with an aromatic ring, a bicycloalkyl, or tricycloalkyl, said bicycloalkyl or tricycloalkyl being an aliphatic saturated hydrocarbon group made of two or three rings, respectively, with at least two carbon atoms being common to each ring, or an azabicycloalkyl group which is a bicycloalkyl group as described above in which one carbon atom is replaced by a nitrogen atom or a group represented by the formula: 
wherein g and h are each an integer of 1 to 4, and Bxe2x80x2 stands for a lower alkyl group, an arylalkyl group, an arylalkyl group substituted by lower alkyl; halogen or a lower alkoxy group, or a pyridylalkyl group, or a pyridylalkyl group substituted with a lower alkyl group, a halogen or a lower alkoxy group; or
R1 and R2 may be combined together to form a 6- or 7-membered ring which may contain a nitrogen or oxygen atom in addition to the nitrogen atom to which R1 and R2 are bonded, and said 6- or 7-membered ring may be substituted with a lower alkyl, arylalkyl, cycloalkylalkyl or heteroarylalkyl group;
R3 represents a hydrogen atom, a lower alkyl group, or a C3-C8 cycloalkyl group;
R4 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom;
n is an integer of 1 to 4, provided that when n is 2, the two R4 groups may form a cyclohexenyl or phenyl ring together with two adjacent carbon atoms constituting the benzene ring; and any pharmacologically acceptable salts thereof as inhibitors of phospholipase A2 activity, particularly cPLA2.
Drugs 1998, Vol. 1, No. 1, pp. 49-50 discloses cPLA2 inhibitors of the type
U.S. Pat. No. 5,453,443 discloses a series of biaryl ketones which are reported to inhibit PLA2 enzymes, but it is not indicated whether these compounds are selective for the cytosolic enzymes or even whether they inhibit the cytosolic enzymes. These compounds have the generic formula 
wherein:
R1 is selected from
(a) hydrogen,
(b) xe2x80x94C1-6alkyl, and
(c) xe2x80x94C1-6alkyl-phenyl;
or wherein R1 and R5 are joined such that together with the carbon atoms to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms; R2 and R3 are each independently selected from
(a) hydrogen,
(b) xe2x80x94C1-6alkyl, and
(c) xe2x80x94C1alkyl-phenyl,
or wherein two R2 or two R3 are joined such that together with the carbon atoms to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms;
R5 is as defined above or is selected from
(a) hydrogen
(b) xe2x80x94C1-6alkyl
(c) xe2x80x94C1-6alkyl-phenyl C1-6alkyl,
(d) xe2x80x94OH
(e) xe2x80x94Oxe2x80x94C1-6alkyl, or
(f) xe2x80x94C1-6alkyl-phenyl C1-6alkyl;
R6 is selected from
(a) hydrogen
(b) xe2x80x94C1-6alkyl
(c) xe2x80x94C1-6alkyl-phenyl, wherein the phenyl is optionally substituted with C1-2alkyl;
(d) xe2x80x94OH,
(e) xe2x80x94Oxe2x80x94C1-6alkyl, or
(f) xe2x80x94Oxe2x80x94C1-6alkyl-phenyl, wherein the phenyl is optionally substituted with C1-2alkyl;
or wherein two R6 are joined to form Oxe2x95x90 or are joined together such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms;
R8, R9 and R14 are each independently selected from
(a) H,
(b) xe2x80x94C1-6alkyl
(c) halo
(d) xe2x80x94CN
(e) xe2x80x94OH
(f) xe2x80x94OC1-6alkyl,
(g) xe2x80x94OC1-6alkyl-phenyl
(h) xe2x80x94SR11 
(i) S(O)R11, or
(j) S(O)2R11;
R10, R15, R16 and R17 are each independently selected from
(a) hydrogen,
(b) xe2x80x94C1-6 alkyl, and
(c) xe2x80x94C1-6 alkyl-phenyl;
R11 is selected from
(a) xe2x80x94C1-6 alkyl,
(b) xe2x80x94C2-6 alkenyl,
(c) xe2x80x94CF3,
(d) -phenyl(R12)2, or
(e) xe2x80x94C2-6 alkenyl-phenyl(R12)2,
R12 is
(a) hydrogen,
(b) xe2x80x94C1-6alkyl,
(c) Cl, F, I or Br;
R13 is perfluoroC1-6alkyl;
A and B are each independently
(a) covalent bond,
(b) O,
(c) S,
(d) S(O), or
(e) S(O)2;
Q is selected from
(a) xe2x80x94CH(OH)R13,
(b) xe2x80x94COR13,
(C) xe2x80x94COR16, or
(d) xe2x80x94C1-4alkylCOCOOR17;
X1 is selected from
(a) xe2x80x94Oxe2x80x94
(b) xe2x80x94Sxe2x80x94
(c) xe2x80x94S(O)xe2x80x94,
(d) xe2x80x94Sxe2x80x94(O)2xe2x80x94;
Z is
(a) H, or
(b) -phenyl-(R14)3,
m is 0, 1, 2, 3 or 4;
n is 2, 3, 4, 5, 6 or 7; and
r and s are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.
J. Prakt. Chem., Vol. 337, pp. 34-37 (1995) discloses the compound of the formula 
Anal. Chem., Vol. 63, No. 6, pp. 596-603 (1991) discloses the compound of the formula 
The present invention is directed to selective cytosolic PLA2 inhibitor compounds of the formula 
wherein
W is CHxe2x95x90CH, CHxe2x95x90N, O or S;
R1 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkylthio, halo, hydroxy, cyano, 
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl, xe2x80x94COOxe2x80x94(C1-C6)alkyl,
CF3, (C1-C6)alkylphenyl, phenyl or phenyl substituted by one or more, preferably 1-3, of (C1-C6)alkyl, xe2x80x94COOxe2x80x94(C1-C6)alkyl, 
xe2x80x83in which
R2 and R3 are as defined above, halo, hydroxy, xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94Sxe2x80x94(C1-C6)alkyl, or (C2-C6)alkenyl;
p is 0, 1 or 2;
A is Vxe2x80x94(Rc)nxe2x80x94;
Rc is a straight or branched chain alkyl group;
n is 0 or an integer of from 1 to 6;
Ra and Rb when taken together form an oxo (xe2x95x90O) group, or Ra and Rb are each independently hydrogen or OH;
V is O, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2, xe2x80x94CONH or NHCO when n is an integer of from 1 to 6 or V is (C2-C6) alkenyl or a bond when n is 0 or an integer of from 1 to 6;
D is xe2x80x94(CH2)m or a bond linking the 
m is an integer of from 1 to 6;
Y is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2; 
xe2x80x83or a bond;
R4 is as defined below for R7;
Z is: 
in which B is: 
X is S or O;
q is an integer from 1 to 6;
R9 is hydrogen or (C1-C6)alkyl;
R10 is hydrogen, CN, NO2, OH, xe2x80x94Oxe2x80x94(C1-C6)alkyl, (C1-C6) alkyl, phenyl or (C1-C6)alkylphenyl;
R5 and R6 are each independently hydrogen or (C1-C18) alkyl;
R7 and R8 are each independently;
(a) hydrogen;
(b) (C1-C18)alkyl;
(c) (C1-C18)alkyl substituted by one or more of
(1) phenyl;
(2) phenyl substituted by 1-5 fluoro, 1-3 (for each of the following phenyl substituents) halo (other than fluoro), 1-3(C1-C6)alkoxy, 1-3(C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6)alkylthio, amino, 1-3 (C1-C6) alkylamino, di(C1-C6)alkylamino, xe2x80x94CO2H, xe2x80x94COOxe2x80x94(C1-C6)alkyl, xe2x80x94SO3H, xe2x80x94SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or 
xe2x80x83in which R2 and R3 are as defined above;
(3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;
(4) heterocyclic substituted by one or more of, preferably 1-3, phenyl, phenyl substituted by 1-3 (for each of the following) halo, (C1-C6)alkoxy, (C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, (C1-C6) alkylamino, di(C1-C6) alkylamino, CO2H, xe2x80x94COOxe2x80x94(C1-C6) alkyl, xe2x80x94SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or 
xe2x80x83in which R2 and R3 are as defined above, (C1-C6) alkyl or (C1-C6) alkyl substituted by one or more, preferably 1-3, phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 (for each of the following) halo, 1-3 (C1-C6) alkoxy, 1-3 (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, 1xe2x80x943 (C1-C6) alkylamino, di(C1-C6) alkylamino, COOH, xe2x80x94COOxe2x80x94(C1-C6) alkyl, xe2x80x94SO3H, xe2x80x94SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or 
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C6) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
(5) carboxy or xe2x80x94COOxe2x80x94(C1-C6) alkyl;
(6) hydroxy, halo, xe2x80x94Oxe2x80x94(C1-C6) alkyl or xe2x80x94Sxe2x80x94(C1-C6) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;
(7) cyano;
(8) halo, trifluoromethyl or trifluoroacetyl;
(9) CH2 Lxe2x80x94R16 in which L is 
xe2x80x83or xe2x80x94Oxe2x80x94SiR16R18R19 or a bond in which R16 and R17 are each independently (C1-C18)alkyl or (C2-C18)alkenyl or (C1-C18)alkyl or (C2-C18)alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3(C1-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (C1-C6)alkylthio, amino, 1-3(C1-C6)alkylamino, 1-3 di(C1-C6)alkylamino, CO2H, 1-3 xe2x80x94COO(C1-C6)alkyl, 
xe2x80x83or xe2x80x94SO2NHR9 in which R9 is hydrogen or (C1-C6)alkyl and R2 and R3 are as defined above;
(b) 
xe2x80x83in which B1 is 
xe2x80x83or a bond;
providing that when B1 is xe2x80x94PO(OR9)2, then R7 becomes R9, and when B1 is 
xe2x80x83or xe2x80x94SO2xe2x80x94, then R7 cannot be hydrogen;
X, q, R5, R6, R7, R8, R9 and R10 are as defined in (a);
(c) 
xe2x80x83in which q, R5 and R6 are as defined above;
R18, R19and R11 are as defined above for R7 and R8 except that they may not be hydrogen, or R18 and R19 taken together with the nitrogen to which they are attached represent a 4, 5- or 6-membered heterocyclic ring and Y, R7 and R11 are as defined above, or R18, R19 and R11 taken together with the nitrogen to which they are attached represent pyridinium, said pyridinium group being unsubstituted or substituted by (C1-C12)alkyl, (C1-C12)alkoxy, amino, (C1-C12)alkylamino, di (C1-C12)alkylamino, 
xe2x80x83xe2x80x94Sxe2x80x94(C1-C12)alkyl, 
xe2x80x83in which R2 and R3 are as defined above, phenyl or phenyl (C1-C10)alkyl;
d) 
xe2x80x83in which R13 is (C1-C18)alkyl or (C1-C18)alkyl substituted by carboxy, 
xe2x80x83in which R2 and R3 are as defined above, hydroxy, xe2x80x94Oxe2x80x94(C1-C6) alkyl, xe2x80x94Oxe2x80x94(C1-C6) alkyl or xe2x80x94Sxe2x80x94(C1-C6) alkyl substituted by 1 or 2 phenyl or substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 (for each of the following phenyl substituents) halo (other than fluoro), (C1-C6) alkoxy, (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, (C1-C6) alkylamino, di(C1-C6) alkylamino, CO2H, COOxe2x80x94(C1-C6) alkyl, SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl or 
xe2x80x83in which R2 and R3 are as defined above;
r is 0 or an integer of from 1 to 3;
R7 is as defined above;
M is xe2x80x94(CH2xe2x80x94)mT where 
xe2x80x83in which R2 is as defined above, xe2x80x94SO2xe2x80x94 or a bond when MR7 is on nitrogen and providing that when 
xe2x80x83then R7 cannot be hydrogen, and 
xe2x80x83or a bond when MR7 is on a carbon atom of the heterocyclic ring;
R14 is hydrogen or (C1-C6)alkyl;
m is 0 or an integer of 1-6; 
wherein Q is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94, and q, R5, R6 and R7 are as defined above, providing that when Q is xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94, R7 cannot be hydrogen;
f) R7 wherein R7 is defined above, providing that when Y is xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94, R7 cannot be hydrogen, and providing that when Y is O and D is a bond, R7 cannot be (C1-C18) alkyl; and
R18 and R19 are phenyl or phenyl substituted by 1-3 halo, (C1-C6) alkoxy, (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, (C1-C6) alkylamino, di(C1-C6) alkylamino, CO2H, xe2x80x94COOxe2x80x94(C1-C6) alkyl, xe2x80x94SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or 
xe2x80x83in which R2 and R3 are as defined above; or pharmaceutically acceptable salts, solvates or prodrugs thereof.
Also provided by this invention are methods for inhibiting cytosolic PLA2 in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound of formula I and methods for using the compounds of formula I to treat various diseases characterized by inappropriate activation of the cytosolic PLA2 enzymes such as asthma, allergic rhinitis, cerebral ischemia, Alzheimer""s Disease, rheumatoid arthritis, acute pancreatitis, inflammatory bowel disease, psoriasis, gout, neutrophil and platelet activation, chronic skin inflammation, shock, trauma-induced inflammation such as spinal cord injury, damage to the skin resulting from UV light or bums and macrophage activation. In further aspects, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier and processes for preparing the compounds of formula I.
The object of this invention was to discover a selective cPLA2 inhibitor which is active, both topically and orally, in treating inflammary disease of the skin and other tissues as well as other chronic and acute conditions which have been linked to inappropriate activation of the cPLA2 enzymes. Preferably such compound would also be devoid of undesirable lipid-perturbing activities associated with skin irritation.
The above-mentioned objectives have been met by the compounds of formula I described above.
In the present application the numbers in the subscript after the symbol xe2x80x9cCxe2x80x9d define the number of carbon atoms a particular group can contain. For example, C1-18alkyl refers to straight and branched chain alkyl groups with 1 to 18 carbon atoms. Similarly, C2-C18 alkenyl refers to a straight or branched unsaturated hydrocarbon group containing from 2 to 18 carbon atoms and at least one carbon-carbon double bond. Likewise, C2-C18 alkynyl refers to a straight or branched unsaturated hydrocarbon group containing from 2 to 18 carbon atoms and at least one carbon-carbon triple bond.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein refers to fluorine, chlorine, bromine or iodine.
Aryl as used herein refers to a C6 monocyclic aromatic ring system or a C9 or C10 bicyclic carbocyclic ring system having one or two aromatic rings such as phenyl or naphthyl. Unless otherwise indicated, xe2x80x9csubstituted arylxe2x80x9d refers to aryl groups substituted with one or more (preferably from 1 to 3) substituents independently selected from (C1-C6)alkyl, haloalkyl, (C1-C6)alkoxy, (C1-C6)alkoxy-carbonyl, (C1-C6)alkanoyl, hydroxy, halo, mercapto, nitro, amino, cyano, (C1-C6)alkylamino, di(C1-C6)alkylamino, carboxy, aryl, aryl (C1-C6)alkyl, aryl (C1-C6)alkoxy, heterocyclic, heterocyclic (C1-C6)alkyl and the like.
The term xe2x80x9cheterocyclicxe2x80x9d as used herein refers to a 4-, 5- or 6-membered ring containing one, two or three heteroatoms selected from N, O and S. The 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized or N-oxidized. The sulfur heteroatoms can be optionally S-oxidized. The term xe2x80x9cheterocyclicxe2x80x9d also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring. Heterocyclics include: pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolidinyl, pyridyl, piperidyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, furyl, dihydrofuranyl, tetrahydrofuranyl, pyranyl, dihydropyranyl, dioxolanyl, thienyl, benzothienyl and diaxanyl.
Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to include such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms, and pharmaceutically acceptable salts thereof.
As mentioned above the invention also includes pharmaceutically acceptable salts of the compounds of formula I. A compound of the invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups. Accordingly, a compound may react with any of a number of inorganic bases, and organic and inorganic acids, to form a pharmaceutically acceptable salt.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcexc-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. Suitable organic bases include trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-xcex2-phenethylamine, 1-ephenamine, N,Nxe2x80x2-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or the like pharmaceutically acceptable amines. The potassium and sodium salt forms are particularly preferred.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
The present invention also includes solvated forms of the compounds of formula I, particularly hydrates, in which the trifluoromethyl ketone group exists as a mixture of ketonic I and hydrated forms II and are each independently interconvertible and pharmacologically active. 
The present invention also includes prodrug forms of the compounds of formula I or II above such as trifluoromethylketone enol ester derivatives, enol phosphate derivatives, cyclic or acylic unsubstituted or substituted O,O-ketals, O,S-ketals, O,N-ketals or S,N-ketals such as cyclic cysteamyl derivatives, cyclic glycolates, thioglycolates, glyoxylates or oxalates, and the like. It also includes trifluoromethylalcohols obtained by chemical reduction of trifluoromethylketones. Such forms are physiologically hydrolyzable groups which are converted in vivo to a pharmacologically active compound of formula I or II, or a crystalline form of such compounds, see scheme below. 
Preferred compounds of formula I are those where the 
substituent is linked to the phenyl ring at the para or meta position, most preferably at the para position.
Preferred embodiments of the compounds of general formula I include
(a) compounds of formula I wherein W is CHxe2x95x90CH, D is a bond linking Y to the ring and Y is xe2x80x94Oxe2x80x94;
(b) compounds of (a) immediately above wherein R1 is benzyl, A is Vxe2x80x94(CH2)nxe2x80x94, V is (C2-C6) alkenyl or a bond, p is 0, 1 or 2, and n is 0 or an integer of from 1 to 6; and
(c) compounds of (b) immediately above wherein A is xe2x80x94(CH2)n, is 0 or an integer of from 1 to 6, and the group xe2x80x94(CH2)nCOCF3 is in the meta or para position of the phenyl ring.
Another preferred embodiment comprises a compound of the formula 
wherein R1 is benzyl; p is 0, 1 or 2; A is Vxe2x80x94(CH2)nxe2x80x94; V is (C2-C6) alkenyl or a bond; n is 0 or an integer of from 1 to 6; Ra and Rb are as defined above and Z is 
in which B is 
or a bond;
X is S or O;
q is an integer of from 1 to 6;
R9 is hydrogen or (C1-C6) alkyl;
R10 is hydrogen, CN, NO2, OH, xe2x80x94Oxe2x80x94(C1-C6) alkyl, (C1-C6) alkyl, phenyl or (C1-C6) alkylphenyl;
R5 and R6 are each independently hydrogen or (C1-C6) alkyl; and R7 and R8 are each independently
a) hydrogen;
b) (C1-C18) alkyl;
c) (C1-C18) alkyl substituted by one or more of, preferably 1-3,
(1) phenyl;
(2) phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6) alkoxy, 1-3 (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, 1-3 (C1-C6) alkylamino, di(C1-C6) alkylamino, xe2x80x94CO2H, xe2x80x94COOxe2x80x94(C1-C6) alkyl; xe2x80x94SO3H, xe2x80x94SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or 
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C6) alkyl;
(3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;
(4) heterocyclic substituted by one or more of, preferably 1-3, phenyl, phenyl substituted by 1-3 halo, (C1-C6)alkoxy, (C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, (C1-C6) alkylamino, di(C1-C6) alkylamino, CO2H, xe2x80x94COOxe2x80x94(C1-C6) alkyl, xe2x80x94SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or 
xe2x80x83in which R2 and R3 are as defined above, (C1-C6) alkyl or (C1-C6) alkyl substituted by one or more, preferably 1-3, phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 halo, 1-3 (C1-C6) alkoxy, 1-3 (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, 1-3 (C1-C6) alkylamino, di(C1-C6) alkylamino, COOH, xe2x80x94COOxe2x80x94(C1-C6) alkyl, xe2x80x94SO3H, xe2x80x94SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or 
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C6) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
(5) carboxy or xe2x80x94COOxe2x80x94(C1-C6) alkyl;
(6) hydroxy, halo, xe2x80x94Oxe2x80x94(C1-C6) alkyl or xe2x80x94S(C1-C6) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;
(7) cyano;
(8) halogen, trifluoromethyl or trifluoroacetyl; or
(9) CH2 Lxe2x80x94R16 in which L is 
xe2x80x83or xe2x80x94Oxe2x80x94SiR16R18R19 or a bond in which R16 and R17 are each independently (C1-C18)alkyl or (C2-C18)alkenyl or (C1-C18)alkyl or (C2-C18)alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3(C1-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (C1-C6)alkylthio, amino, 1-3(C1-C6)alkylamino 1-3 di(C1-C6)alkylamino, CO2H, 1-3 xe2x80x94COO(C1-C6)alkyl, 
xe2x80x83or xe2x80x94SO2NHR9 in which R9 is hydrogen or (C1-C6)alkyl and R2 and R3 are as defined above; and R18 and R19 are phenyl or phenyl substituted by 1-3 halo, (C1-C6) alkoxy, (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, (C1-C6) alkylamino, di(C1-C6) alkylamino, CO2H, xe2x80x94COOxe2x80x94(C1-C6) alkyl, xe2x80x94SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or 
xe2x80x83in which R2 and R3are as defined above; or pharmaceutically acceptable salts, solvates or prodrugs thereof. 
in which B1 is 
xe2x80x83or a bond; providing that when B1 is xe2x80x94PO(OR9)2, then R7 becomes R9, and when 
xe2x80x83or xe2x80x94SO2xe2x80x94, then R7 cannot be hydrogen; and
X, q, R5, R6, R7, R8, R9 and R10 are as defined above in (a); 
xe2x80x83in which R13 is (C1-C18)alkyl or (C1-C18)alkyl substituted by carboxy, 
xe2x80x83in which R2 and R3 are as defined above, hydroxy, xe2x80x94Oxe2x80x94(C1-C6) alkyl, xe2x80x94Oxe2x80x94(C1-C6) alkyl or xe2x80x94Sxe2x80x94(C1-C6) alkyl substituted by 1 or 2 phenyl or substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 halo (other than fluoro), (C1-C6) alkoxy, (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, (C1-C6) alkylamino, di(C1-C6) alkylamino, CO2H, COOxe2x80x94(C1-C6) alkyl, SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl 
xe2x80x83in which R2 and R3 are as defined above;
r is 0 or an integer of from 1 to 3;
R7 is as defined above;
M is xe2x80x94(CH2xe2x80x94)mT where 
xe2x80x83in which R2 is as defined above, xe2x80x94SO2xe2x80x94 or a bond when MR7 is on nitrogen and providing that when 
xe2x80x83then R7 cannot be hydrogen, and 
xe2x80x83or a bond when MR7 is on a carbon atom of the heterocyclic ring;
R14 is hydrogen or (C1-C6)alkyl;
m is 0 or an integer of 1-6; 
xe2x80x83wherein Q is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, or xe2x80x94SO2xe2x80x94 and q, R5, R6 and R7 are as defined above, providing that when Q is xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94, R7 cannot be hydrogen; or
(e) R7 where R7 is as defined above, providing that when Y is xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94, R7 cannot be hydrogen and providing that when Y is O, R7 cannot be (C1-C18) alkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
Another preferred embodiment comprises a compound of the formula 
wherein n is 0 or an integer of from 1 to 6, the substituent xe2x80x94(CH2)nCOCF3 is in the meta or para position of the phenyl ring and Z is 
in which B is 
or a bond; X is S or O; q is an integer of from 1 to 6; and R5, R6, R7 and R8 are as defined above; or a pharmaceutically acceptable salt, hydrate or prodrug thereof.
Another preferred embodiment comprises a compound of the formula 
in which R1 is benzyl; p is 0, 1 or 2; n is 0 or an integer of from 1 to 6; the substituent xe2x80x94(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is 
in which B1 is 
or a bond;
q is an integer of from 1 to 6;
X is S or O;
and R5, R6, R7, R8, R9 and R10 are as defined above; or a pharmaceutically acceptable salt, solvate or prodrug thereof. Within this embodiment, it is preferred that the substituent xe2x80x94(CH2)nCOCF3 is in the para position of the phenyl ring, R5 and R6 are both hydrogen, q is 1,2 or 3, n is 2 or 3, B1 is 
xe2x80x83and R7 and R8 are each independently hydrogen or (C1-C18) alkyl. Especially preferred are compounds where q is 1, n is 2 and 
Another preferred embodiment comprises a compound of the formula 
wherein n is 0 or an integer of from 1 to 6; the substituent xe2x80x94(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is 
in which R13, r, M and R7 are as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
Another preferred embodiment comprises a compound of the formula 
which n is 0 or an integer of from 1 to 6, the substituent xe2x80x94(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is 
wherein q is an integer of from 1 to 6; R5 and R6 are each independently hydrogen or (C1-C18)alkyl; and Q and R7 are as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
Another preferred embodiment comprises a compound of the formula 
in which n is 0 or an integer of from 1 to 6; the substituent xe2x80x94(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is
(a) hydrogen;
(b) (C1-C18)alkyl substituted by one or more, preferably 1-3, of
(1) phenyl;
(2) phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3(C1-C6)alkoxy, 1-3(C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6)alkylthio, amino, 1-3 (C1-C6) alkylamino, di(C1-C6)alkylamino, xe2x80x94CO2H, xe2x80x94COOxe2x80x94(C1-C6)alkyl, xe2x80x94SO3H, xe2x80x94SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or 
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C6) alkyl;
(3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;
(4) heterocyclic substituted by one or more, preferably 1-3, of phenyl, phenyl substituted by 1-3 halo, (C1-C6)alkoxy, (C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, (C1-C6) alkylamino, di(C1-C6) alkylamino, CO2H, xe2x80x94COOxe2x80x94(C1-C6) alkyl, xe2x80x94SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or 
xe2x80x83in which R2 and R3 are as defined above, (C1-C6) alkyl or (C1-C6) alkyl substituted by one or more, preferably 1-3, phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 halo, 1-3 (C1-C6) alkoxy, 1-3 (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, 1-3 (C1-C6) alkylamino, di(C1-C6) alkylamino, COOH, xe2x80x94COOxe2x80x94(C1-C6) alkyl, xe2x80x94SO3H, xe2x80x94SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or 
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C6) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
(5) carboxy or xe2x80x94COOxe2x80x94(C1-C6) alkyl;
(6) hydroxy, halo, xe2x80x94Oxe2x80x94(C1-C6) alkyl or xe2x80x94Sxe2x80x94(C1-C6) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;
(7) cyano;
(8) halogen, trifluoromethyl or trifluoroacetyl;
(9) CH2 Lxe2x80x94R16 in which L is 
xe2x80x83or xe2x80x94Oxe2x80x94SiR16R18R19 or a bond in which R16 and R17 are each independently (C1-C18)alkyl or (C2-C18)alkenyl or (C1-C18)alkyl or (C2-C18)alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3(C1-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (C1-C6)alkylthio, amino, 1-3(C1-C6)alkylamino, 1-3 di(C1-C6)alkylamino, CO2H, 1-3 xe2x80x94COO(C1-C6)alkyl, 
xe2x80x83or xe2x80x94SO2NHR9 in which R9 is hydrogen or (C1-C6)alkyl and R2 and R3 are as defined above; and R18 and R19 are phenyl or phenyl substituted by 1-3 halo, (C1-C6) alkoxy, (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, (C1-C6) alkylamino, di(C1-C6) alkylamino, CO2H, xe2x80x94COOxe2x80x94(C1-C6) alkyl, xe2x80x94SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or 
xe2x80x83in which R2 and R3 are as defined above; or pharmaceutically acceptable salts, solvates or prodrugs thereof.
A most preferred embodiment of the present invention comprises a compound of the formula 
wherein R1 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkylthio, halo, hydroxy, cyano, 
in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl, xe2x80x94COOxe2x80x94(C1-C6)alkyl, CF3, (C1-C6)alkylphenyl, phenyl or phenyl substituted by one or more, preferably 1xe2x80x943, of (C1-C6)alkyl, xe2x80x94COOxe2x80x94(C1-C6)alkyl, 
in which R2 and R3 are as defined above, halo, hydroxy, xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94Sxe2x80x94 (C1-C6)alkyl or (C2-C6)alkenyl;
p is 0, 1 or 2;
n is 0 or an integer of from 1-6; and
Z is
(C1-C18)alkyl, (C2-C18)alkenyl or (C2-C18)alkynyl in which one or more carbon atoms in such alkyl, alkenyl or alkynyl group is optionally replaced by S, SO, SO2, 
xe2x80x83in which R28 and R29 are each independently hydrogen, xe2x80x94COCF3, xe2x80x94CO-phenyl, xe2x80x94COOxe2x80x94(C1-C6)alkyl, 
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl, (C1-C18)alkyl or (C1-C18)alkyl substituted by one or more of phenyl or phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3 (C1-C6)alkyl, 1-3 nitro, 1-3 cyano, 1-3 hydroxy, 1-3 trifluoromethyl, 1-3 (C1-C6)alkylthio, 1-3 amino, 1-3 (C1-C6)alkylamino, 1-3 di (C1-C6)alkylamino, 1-3 carboxyl, 1-3 xe2x80x94COOxe2x80x94(C1-C6)alkyl, 1-3 xe2x80x94SO3H, 1-3 xe2x80x94SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or 
in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl; providing that when Yxe2x80x2 is O, Z cannot be (C1-C18)alkyl; or a pharmaceutically acceptable salt or prodrug thereof.
Within the above-mentioned most preferred embodiment, the most preferred compounds of the present invention are those in which Z is 
in which R35 and R36 are phenyl or phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3 (C1-C6)alkyl, 1-3 nitro, 1-3 cyano, 1-3 hydroxy, 1-3 trifluoromethyl, 1-3 (C1-C6)alkylthio, 1-3 amino, 1-3 (C1-C6)alkylamino, 1-3 di (C1-C6)alkylamino, 1-3 carboxyl, 1-3 xe2x80x94COOxe2x80x94(C1-C6)alkyl, 1-3 xe2x80x94SO3H, 1-3 xe2x80x94SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or 
in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl; 
which R35 and R36 are as defined above; 
in which nxe2x80x2 is 0, 1 or 2 and R35 and R36 are as defined above; 
in which nxe2x80x2, R35 and R36 are as defined above; or pharmaceutically acceptable salts and/or prodrugs thereof.
Another preferred embodiment comprises a compound of the formula 
in which n is 0, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.
Preferred embodiments comprise a compound selected from those of the following 
wherein
(a) R25 is xe2x80x94(CH2)3CH3;
(b) R25 is xe2x80x94(CH2)3CO2C2H5;
(c) R25 is xe2x80x94(CH2)3CONHC2H5;
(d) R25 is xe2x80x94COCF3;
(e) R25 is xe2x80x94COC6H5; and
(f) R25 is xe2x80x94PO(OC2H5)2; or a pharmaceutically acceptable salt thereof.
Still other preferred embodiments comprise a compound of the formula 
wherein
(a) R20 is xe2x80x94CO(CH2)10CH3;
(b) R20 is xe2x80x94COCH(p-chlorophenyl)2; and
(c) R20 is xe2x80x94SO2(CH2)11CH3; or a pharmaceutically acceptable salt thereof.
Still other preferred embodiments comprise a compound selected from those of the following 
wherein
(a) Xxe2x80x3 and Xxe2x80x2xe2x80x3 are Cl;
(b) Xxe2x80x3 and Xxe2x80x2xe2x80x3 are F;
(c) Xxe2x80x3 and Xxe2x80x2xe2x80x3 are OCH3; and
(c) Xxe2x80x3 is Cl and Xxe2x80x2xe2x80x3 is OCH3; or a pharmaceutically acceptable salt thereof.
Another preferred embodiment comprises a compound of the formula 
wherein
(a) n is 1 and R21 is OCH3;
(b) n is 1 and R21 is Cl;
(c) n is 2 and R21 is OCH3; and
(d) n is 1-4 and R21 is OCH3 or Cl; or a pharmaceutically acceptable salt thereof.
Another preferred embodiment comprises a compound of the formula 
wherein
(a) R22 is hydrogen and R23 is Cl; or
(b) R22 is xe2x80x94CO2CH3 and R23 is xe2x80x94OCH3; or a pharmaceutically acceptable salt thereof.
Another preferred embodiment comprises a compound of the formula 
wherein R24 is Cl or xe2x80x94OCH3; or a pharmaceutically acceptable salt thereof.
Another preferred embodiment comprises a compound of the formula 
wherein
(a) R26 and R27 are both CH3 or (C1-C6)alkyl-CF3;
(b) R26 and R27 are both Cl, F or Br;
(c) R26 and R27 are both OCH3 or SCH3;
(d) R26 is Cl and R27 is OCH3; or
(e) R26 and R27 are both xe2x80x94COOxe2x80x94(C1-C6)alkyl; or a pharmaceutically acceptable salt thereof.
Still other preferred embodiments comprise a compound selected from those of the following 
wherein
(a) n is 0;
(b) n=1; and
(c) n=2; or a pharmaceutically acceptable salt thereof.
Still other preferred embodiments comprise a compound selected from those of the formula 
wherein
(a) n=0;
(b) n=1; and
(c) n=2; or a pharmaceutically acceptable salt thereof.
Some specific preferred embodiments of the present invention are: 
wherein
(a) R26 and R27 are both CH3 or xe2x80x94(C1-C6)alkyl-CF3;
(b) R26 and R27 are both Cl, F or Br;
(c) R26 and R27 are both OCH3 or SCH3;
(d) R26 is Cl and R27 is OCH3; or
(e) R26 and R27 are both xe2x80x94COOxe2x80x94(C1-C6)alkyl.
Especially preferred embodiments of the present invention include: 
The present inventors have discovered that many of the compounds of general formula I, although exhibiting good in vitro potency, are metabolized in vivo resulting in a significant decrease in in vivo activity. However, if the xe2x80x9cAxe2x80x9d substituent of the formula I compounds is a group of the formula 
which V is O, S, SO, SO2, xe2x80x94CONHxe2x80x94 or xe2x80x94NHCOxe2x80x94 and Rc is hydrogen or CH3, the metabolic stability of the compounds is surprisingly increased, resulting in good in vivo as well as in vitro potency.
In view of this discovery, the present invention in another aspect provides compounds of the general formula 
in which Rxe2x80x2 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkylthio, halo, hydroxy, cyano, 
in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl, xe2x80x94COOxe2x80x94(C1-C6)alkyl, CF3, (C1-C6)alkylphenyl, phenyl or phenyl substituted by one or more of (C1-C6)alkyl, xe2x80x94COOxe2x80x94(Cl-C6)alkyl, 
in which R2 and R3 are as defined above, halo, hydroxy, xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94Sxe2x80x94(C1-C6)alkyl or (C2-C6)alkenyl;
p is 0, 1 or 2;
Vxe2x80x2 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NHCOxe2x80x94 or xe2x80x94CONHxe2x80x94;
Rc and Rd are each independently hydrogen or methyl;
Ra and Rb when taken together form an oxo (xe2x95x90O) group, or Ra and Rb are each independently hydrogen or OH; 
xe2x80x83or CH2 in which Rd is hydrogen, xe2x80x94COCF3, xe2x80x94COxe2x80x94C6H5, xe2x80x94COOxe2x80x94(C1-C6)alkyl, 
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl, (C1-C18)alkyl or (C1-C18)alkyl substituted by one or more of phenyl or phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3 (C1-C6)alkyl, 1-3 nitro, 1-3 cyano, 1-3 hydroxy, 1-3 trifluoromethyl, 1-3 (C1-C6)alkylthio, 1-3 amino, 1-3 (C1-C6)alkylamino, 1-3 di (C1-C6)alkylamino, 1-3 carboxyl, 1-3 xe2x80x94COOxe2x80x94(C1-C6)alkyl, 1-3 xe2x80x94SO3H, 1-3 xe2x80x94SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or 
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl; and
Zxe2x80x2 is (C1-C18)alkyl, (C2-C18)alkenyl or (C2-C18)alkynyl in which one or more carbon atoms in such alkyl, alkenyl or alkynyl group are optionally replaced by S, SO, SO2, 
xe2x80x83in which R33 and R34 are each independently hydrogen, xe2x80x94COCF3, xe2x80x94COxe2x80x94C6H5, xe2x80x94COOxe2x80x94(C1-C6)alkyl 
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C18)alkyl, (C1-C18)alkyl, (C1-C18)alkyl substituted by one or more of phenyl or phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3 (C1-C6)alkyl, 1-3 nitro, 1-3 cyano, 1-3 hydroxy, 1-3 trifluoromethyl, 1-3 (C1-C6)alkylthio, 1-3 amino, 1-3 (C1-C6)alkylamino, 1-3 di (C1-C6)alkylamino, 1-3 carboxyl, 1-3 xe2x80x94COOxe2x80x94(C1-C6)alkyl, 1-3 xe2x80x94SO3H, 1-3 xe2x80x94SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or 
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl; or (C1-C18)alkyl substituted at a terminal carbon atom by 
xe2x80x83in which R35, R36 and R37 are each independently (C1-C6)alkyl, aryl, aryl (C1-C6)alkyl, heterocyclic or heterocyclic (C1-C6)alkyl in which the aryl or heterocyclic rings may be optionally substituted by 1-3 halo, (C1-C6)alkoxy, (C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6)alkylthio, amino, di (C1-C6)alkylamino, xe2x80x94CO2H, xe2x80x94COOxe2x80x94(C1-C6)alkyl, xe2x80x94SO3H, xe2x80x94SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl or 
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl, providing that when Yxe2x80x2 is O, Zxe2x80x2 cannot be (C1-C18)alkyl; or pharmaceutically acceptable salts and/or prodrugs thereof.
Within the compounds encompassed by general formula III, a preferred embodiment of the present invention comprises the compounds in which Vxe2x80x2 is in the p-position and Zxe2x80x2 is 
xe2x80x83in which nxe2x80x2 is 0, 1 or 2 and R33 and R34 are phenyl or phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3 (C1-C6)alkyl, 1-3 nitro, 1-3 cyano, 1-3 hydroxy, 1-3 trifluoromethyl, 1-3 (C1-C6)alkylthio, 1-3 amino, 1-3 (C1-C6)alkylamino, 1-3 di(alkylamino), 1-3 carboxy, 1-3 xe2x80x94COOxe2x80x94(C1-C6)alkyl, 1-3 xe2x80x94SO3H, 1-3 xe2x80x94SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or 
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl; 
xe2x80x83in which nxe2x80x2 is 0, 1 or 2 and R33 and R34 are as defined above;
(c) 
xe2x80x83in which and R33 and R34 are as defined above;
(d) xe2x80x94(CH2)2xe2x80x94Sxe2x80x94(CH2)2xe2x80x94CR33R34 
xe2x80x83in which and R33 and R34 are as defined above;
(e) 
xe2x80x83in which and R33 and R34 are as defined above; and
(f) 
xe2x80x83in which and R33 and R34 are as defined above, including pharmaceutically acceptable salts and prodrugs thereof.
Specific preferred embodiments of the present invention comprise the following compounds: 
or a pharmaceutically acceptable salt or prodrug thereof.
The compounds of the present invention can be prepared by various methods which are known in the art. Illustrative methods of preparation are provided in the reaction schemes which follow and in the Examples. 
Preparation of compounds of formula I may be accomplished via one or more of the synthetic schemes which are described below.
Scheme 1
Scheme I shows a method of preparing compounds of general structure 6. Reaction of a phenol 2 bearing a protected carboxylate group with an alcohol 3, triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate under Mitsunobu conditions (O. Mitsunobu, Synthesis, 1, 1981) in a solvent such as tetrahydrofuran or benzene gave the ether 4. Alternatively, the phenol 2 can be alkylated with a substituted alkyl halide (RX) and a base such as potassium carbonate in a solvent such as acetonitrile or dimethylformamide to give the ether 4. The ester group of 4 is then saponified to the acid 5 by treatment with a base such as sodium hydroxide or potassium hydroxide in a solvent such as aqueous ethanol followed by neutralization with a diluted acid. The acid 5 is then treated with oxalyl chloride or thionyl chloride in a solvent such as dichloromethane to give an intermediate acid chloride. The acid chloride is then treated with trifluoroacetic anhydride and a base such as pyridine following conditions similar to those used by S. Z. Zard (Tetrahedron 51, 2573-2584, 1995) to give the trifluoromethyl ketone 6.
Scheme 2
Scheme 2 describes a method of preparing compounds of structure 12. Reaction of an iodo-substituted phenol 7 with a dibromo alkane of structure Br(CH2)nBr in the presence of a base such as potassium carbonate gives 8. The bromide 8 is then displaced with a mono or disubstituted amine in the presence of sodium iodide in a solvent such as isopropanol to give 9 or 10. Alternatively, compound 10 can also be obtained under Mitsunobu conditions as described in Scheme 1. Tertiary amines 10 are also obtained by reaction of 9 with various aldehydes RCHO by reaction with a reducing agent such as sodium cyanoborohydride in a solvent such as methanol. Similar tertiary amines 10 are also prepared by reaction of 9 with an iodo compound R(CH2)nI in the presence of a base such as potassium carbonate in a solvent such as isopropanol.
Reaction of secondary amine 9 with a Michael-type acceptor CH2xe2x95x90CH2-EWG such as ethyl acrylate or acrylonitrile in a solvent such as ethanol also yields substituted amines 10. Reaction of iodophenol 10 with 4,4,4-trifluorobut-1-en-3-ol (J. A. Pegolotti and W. G. Young, J. Am. Chem. Soc., 1961, 83, 3251), under Heck-type conditions (T. Jeffery, J. Chem. Soc. Chem. Commun., 1287, 1984) in the presence of a palladium catalyst such as palladium (II) acetate in a solvent such as N,N-dimethylformamide gives the allylic alcohol 11. Hydrogenation of this allylic alcohol in the presence of a catalyst such as palladium on activated carbon in a solvent such as ethyl acetate gave an intermediate alcohol which was oxidized to the ketone 12 with the Dess-Martin periodinane (D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155) in a solvent such as dichloromethane.
Scheme 3
Scheme 3 describes a method of preparing quaternary structures of type 14 and 15. The tertiary amine 13 is alkylated with an alkyl iodide such as methyl iodide or ethyl iodoacetate in a solvent such as isopropanol to give the quaternary amine 14. In the case where one of the R groups contains an ester group, saponification with a base such as potassium hydroxide in a solvent such as aqueous ethanol gives the zwitterionic species 15.
Scheme 4
Scheme 4 shows a method of preparing various trifluoromethyl ketones 23 from intermediates in which the trifluoromethyl ketone is protected as a ketal group. Starting from the acid 16 which is commercially available, the trifluoromethyl ketone 17 is prepared using the method described in Scheme 1. The methyl ether 17 is then cleaved with boron tribromide in a solvent such as dichloromethane to give the phenol 18. The ketone group is then protected as a ketal 19 by reaction with an orthoester such as trimethyl orthoformate catalyzed by an acid such as trifluoromethanesulfonic acid and in solvents such as nitromethane and methanol. The phenol 19 is then treated as described for Z in Scheme 2 to give 20, 21 and 22. The protected trifluoromethyl ketone in 22 allows various modifications on R1 such as reduction of an ester group with lithium aluminum hydride or diisobutyl aluminum hydride. The ketal group is then cleaved with an acid such as trifluoroacetic acid to give 23.
Scheme 5
Scheme 5 describes preparation of tertiary amines by alkylation of intermediate 21 obtained in Scheme 4 by reaction with an alkyl iodide such as iodopropane in a solvent such as isopropanol and in the presence of a hindered base such as N,N-diisopropylethylamine. The ketal 24 is then cleaved as described in Scheme 4 to give the trifluoromethyl ketone 25.
Scheme 6
Scheme 6 describes preparation of a variety of trifluoromethyl ketones 27 starting from the phenol 19 obtained in Scheme 4. Reaction of 19 with various alcohols of structure ROH under the Mitsunobu conditions described in Scheme 1 gave 26. Deprotection of the ketal group as described in Scheme 4 gives 27 possessing a variety of ether substituents.
Scheme 7
Scheme 7 shows a synthetic route to acylated or sulfonylated amines 33. Reaction of 4-hydroxybenzaldehyde with a t-butoxycarbonyl-protected amino-alcohol such as 29 under Mitsunobu conditions similar to those described in Scheme 1 gives the aldehyde 30. Aldol condensation of 30 with 1,1,1-trifluoroacetone catalyzed by piperidine and acetic acid using conditions similar to those used by R. S. H. Liu (Tetrahedron Lett., 26, 2873, 1985) gave the enone 31. The enone 31 was then hydrogenated in the presence of a catalyst such as palladium on barium sulfate and treated with Dess-Martin periodinane as described in Scheme 2 to re-oxidize the partially reduced carbonyl group to give 32. The t-butoxycarbonyl-protected amino derivative 32 is then treated with an acid such as trifluoroacetic acid in a solvent such as dichloromethane to give an intermediate amine as a trifluoroacetate salt. This amine is then acylated with various acyl chlorides such as palmitoyl chloride under Schotten-Baumann conditions in a mixture of solvents such as tetrahydrofuran and saturated aqueous sodium acetate to give amide 33. Alternatively, the amine trifluoroacetate salt can be treated with an alkylsulfonyl chloride such as 1-heptanesulfonyl chloride or an alkyl isothiocyanate such as N-decyl isothiocyanate in presence of a base such as triethylamine and in a solvent such as dichloromethane to give a sulfonamide or a thiourea respectively.
Scheme 8
Scheme 8 describes a method of preparing amides of structure 39 which are regioisomers of structures described in Scheme 7. 4-Hydroxybenzaldehyde was treated with 1,1,1-trifluoroacetone as described in Scheme 7 and alkylated with a bromoester such as t-butyl bromoacetate in the presence of a base such as potassium carbonate and in a solvent such as acetone to give 36. Alternatively 36 can be obtained via the same sequence of steps but in inverse order. The phenol 34 can also be acylated with various acid chlorides such as a palmitoyl chloride to give ester derivatives such as 36b. The t-butyl protecting group of 36 is then cleaved with an acid such as trifluoroacetic acid in dichloromethane to give the acid 37. This acid is then reacted with primary and secondary amines such as dodecylamine in the presence of a condensing agent such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline (EEDQ) to give the amide 38. Reduction and oxidation of the enone as described in Scheme 7 gave the amide 39. Alternatively, the enone 36 can be reduced first to 40 and then cleaved as above to the acid 41. The acid 41 is then treated with oxalyl chloride in dichloromethane to give an intermediate acid chloride. Reaction of this acid chloride with primary and secondary amines such as p-chlorobenzhydrylamine hydrochloride in a mixture of tetrahydrofuran and saturated aqueous sodium acetate also gives amides of structure 39.
Scheme 9
Scheme 9 describes a method for making compounds of structure 46, 47 and 48 which contain a sulfur atom. Reaction of an alcohol 43 which contains a sulfur atom, usually obtained by reaction of a thiol with a halogen-substituted alcohol, with phenol 42 under Mitsunobu conditions as described in Scheme 1 gives the ether 44. Preparation of the trifluoromethylketone 46 is then achieved via the two-step sequence also described in Scheme 1. Oxidation of 46 with a peracid such as m-chloroperbenzoic acid gives the sulfone 47. Oxidation of 46 with sodium periodate in a mixture of methanol and water affords the sulfoxide 48.
Preparation of compounds of formula III may be accomplished via one or more of the synthetic schemes which are described below. 
Scheme A
Scheme A describes a method of preparing compounds of generic structure III. Reaction of phenol 1 (X=O) or thiophenol 1 (X=S) in which P is a protecting group such as tert-butyl diphenylsilyl with a bromo ester such as methyl bromoacetate, methyl bromomethylacetate or methyl bromodimethylacetate in a solvent like acetonitrile or N,N-dimethylformamide in presence of a base such as potassium carbonate affords 2. Deprotection of 2 with a reagent such as tetrabutyl ammonium fluoride gave the alcohol 2 (P=H) that was activated via a group like a mesyloxy to give 3 (L=Ms). Reaction of 3 with a secondary amine R33R34NH in a solvent such as acetonitrile gave the amine 4. Reaction of 4 with a trimethylsilylfluoroalkyl reagent such as trifluoro methyltrimethylsilane in a solvent such as toluene using a catalyst like tetrabutylammonium fluoride gave, after aqueous hydrolysis, ketone 5. Alternatively, the ester 4 can be saponified to the acid by a base such as potassium hydroxide and in a solvent such as aqueous ethanol. The acid can be reacted with a reagent such as oxalyl chloride to give an intermediate acid chloride which is then treated with an anhydride such as trifluoroacetic anhydride and a base such as pyridine in a solvent like toluene to give the ketone 5.
When Rc is a methyl group and it is desired to have a chiral compound, an alternative approach may be used. Hence, the aldehyde of type 6 may be converted to the amine 7 via reductive amination conditions by the reaction of various amines in presence of a reducing agent such as triacetoxyborohydride or sodium cyanoborohydride in an inert solvent such as dichloromethane or 1,2-dichloromethane. The resulting thiol or phenol 7 was then submitted to a Mitsunobu reaction with a chiral methyl lactate in presence of triphenylphosphine and diisopropyl azodicarboxylate to give compound 8. Subsequent conversion into the trifluoromethylketone 9 by treatment with trifluoromethyltrimethylsilane in a solvent such as toluene and using a catalyst like tetrabutylammonium fluoride may then be performed. Alternatively, the methyl ester in 8 may be saponified to the corresponding acid by conditions known in the art and subsequently transformed to the acid chloride in presence of oxalyl chloride. Treatment with trifluoroacetic anhydride and a base such as pyridine in a solvent like toluene afford the ketone 9. 
Scheme B describes a method of preparing compounds of general structure 17. Reaction of 10 with a beta-substituted amino or thio or silyloxy ethanol of general formula R1CH2CH2OH under Mitsunobu conditions in a solvent like toluene yielded respectively the amine 11, the sulfide 12 or the silyl derivative 13. Saponification of 11, 12 or 13 with a base such as potassium hydroxide in a solvent such as aqueous ethanol gave the acid 14. The acid 14 can be reacted with reagent such as oxalyl chloride in a solvent such as dichloromethane to give an intermediate acid chloride. Reaction of this acid chloride with an aminotrifluoroalcohol of general formula 15 (R5=H, CH3) in a solvent like tetrahydrofuran and aqueous sodium bicarbonate yielded the amide 16. Reaction of 16 with an oxidant such as 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) or under Swern conditions (dimethylsulfoxide-oxalyl chloride) gave the ketone 17.